Project Brief Summary There is growing evidence implicating the endogenous cannabinoid system in mediating neural processes involved in opioid use/addiction and pain. Preclinical and preliminary studies in humans suggest that cannabidiol (CBD) may be helpful in reducing opioid use and decreasing pain in patients with CNCP syndromes but no studies have yet been conducted of the effects of CBD in humans with CNCP maintained on COT. This double-blind, placebo-controlled, proof-of-concept trial is designed to compare effects of oral CBD 600mg to placebo in 40 outpatients with CNCP syndromes (without co-occurring OUD), maintained on stable moderate to high-dose opioid analgesics for a minimum of 3-months, and motivated to decrease their opioid analgesic maintenance dose. The trial duration will be 6-months and will include a 4-month treatment period (following randomization) of daily CBD 600mg vs placebo, followed by 2 months off of study medication or placebo. Safety and tolerability of CBD will be assessed throughout the trial. Opioid analgesic maintenance dose and pain will be assessed at baseline and longitudinally. Changes in several potential mediators of treatment effect (change in opioid maintenance dose) will be measured (at baseline and longitudinally) including: pain, psychological domains (depression, anxiety, sleep), motivation to change dose of opioid maintenance medication, and markers of opioid misuse/addiction (i.e. craving, withdrawal symptoms). CBD will be administered on top of treatment as usual (i.e. COT) for outpatients with CNCP syndromes. This would be the first clinical trial exploring the effects of CBD in patients with CNCP syndromes (without OUD but at risk for developing an OUD), maintained on COT, and to assess its safety when co- administered with opioid analgesics. The proposed study is highly innovative in using CBD to treat the opioid use domain in patients with CNCP on COT, in an attempt to reduce the potential harms associated with moderate to high-dose COT. Further, it is innovative because CBD has mechanisms of action that are different from medications currently used in the treatment of pain, and also in the treatment of OUDs which could affect the basic neurobiology of opioid misuse/addiction including reductions in intoxication, withdrawal, cue-induced craving and drug seeking behaviors, stress responsivity, and impulsivity. Animal and human trials suggest the possibility that sustained disease-modifying changes could occur as a result of relatively brief treatment duration with CBD, which would represent a novel approach in using a pharmacologic intervention to prevent OUD in CNCP on COT. Demonstration of clinically meaningful reductions in opioid use and pain in patients with CNCP on moderate to high-dose COT could have an enormous impact in reducing adverse outcomes (i.e. opioid addiction and overdose fatalities) and improving quality of life, as well as advancing knowledge of the neurobiological basis of the intersection between chronic pain and opioid use/misuse.